Lynozyfic Drug Information
Generic name: LINVOSELTAMAB-GCPT
Bispecific B Cell Maturation Antigen-directed CD3 T Cell Engager [EPC]
Uses of Lynozyfic
LYNOZYFIC is indicated for the treatment of adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody. This indication is approved under accelerated approval based on response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).
Dosage & Administration of Lynozyfic
Important Administration Instructions Administer
LYNOZYFIC intravenously according to the step-up schedule to reduce the incidence and severity of cytokine release syndrome (CRS). Administer only as an intravenous infusion after dilution in 0.9% Sodium Chloride Injection. Administer pretreatment medications.
LYNOZYFIC should be administered by a healthcare provider with immediate access to emergency equipment and appropriate medical support to manage severe reactions such as cytokine release syndrome (CRS), infusion-related reactions (IRR), and neurologic toxicity, including ICANS. Due to the risk of CRS and neurologic toxicity, including ICANS, patients should be hospitalized for 24 hours after administration of the first step-up dose, and for 24 hours after administration of the second step-up dose.
Recommended Dosage
The recommended dosage for LYNOZYFIC is presented in Table 1. In patients who experience CRS, ICANS, or neurologic adverse reactions, refer to Tables 3, 4, and 5, respectively, for recommendations regarding administration of the next LYNOZYFIC dose. Continue treatment until disease progression or unacceptable toxicity.
The recommended dosing schedule for LYNOZYFIC is provided in Table 1. In patients who have achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of
Recommended Pretreatment Medications Administer the following pre-treatment medications before each dose of the LYNOZYFIC step-up dosing schedule, which includes step-up dose 1, step-up dose 2, and the first treatment dose, the second treatment dose, and if indicated, subsequent treatment doses (see Tables 1, 2, and 3 ), to reduce the risk of CRS and/or IRR: acetaminophen (or equivalent) 650 mg to 1,000 mg orally 30 to 60 minutes prior to infusion diphenhydramine (or equivalent) 25 mg orally or intravenously 30 to 60 minutes prior to infusion dexamethasone (or equivalent) intravenously 1 to 3 hours prior to infusion 40 mg dexamethasone (or equivalent) before step-up dose 1, step-up dose 2, and the first full treatment dose Once a treatment dose of LYNOZYFIC is tolerated without CRS and/or IRR with 40 mg dexamethasone (or equivalent), administer 10 mg dexamethasone (or equivalent) prior to the subsequent LYNOZYFIC treatment dose Pre-treatment medications may be discontinued once a treatment dose of LYNOZYFIC is tolerated without CRS and/or IRR following pre-treatment with 10 mg dexamethasone (or equivalent), acetaminophen (or equivalent), and diphenhydramine (or equivalent) as described.
Restarting LYNOZYFIC After Dosage Delay Table 2 provides recommendations for restarting therapy after a dose delay. Refer to Table 3, Table 4, and Table 5 for recommendations about management of CRS, ICANS, or other adverse reactions. Table 2: Recommendations for Restarting Therapy with LYNOZYFIC After a Dose Delay Last Dose Administered Time since the last dose administered Consider benefit-risk of restarting LYNOZYFIC in patients who require a dose delay of more than 30 days.
Action for next dose. (For CRS/IRR or ICANS, refer to the dose modifications in Table 3, Table 4, and Table 5.) NOTE: Administer pre-treatment medications prior to step-up dose 1, step-up dose 2, the first treatment dose, the second treatment dose, and if indicated, subsequent treatment doses. s Table 3 describes the management of CRS. Table 4 describes the management of ICANS. Table 5 describes the management of other adverse reactions.
Cytokine Release Syndrome Identify CRS based on clinical presentation. Evaluate and treat other causes of fever, hypoxia, and hypotension. If CRS is suspected, withhold LYNOZYFIC until CRS resolves.
CRS should be managed according to the recommendations in Table 3 and per current practice guidelines. Supportive therapy for CRS should be administered, which may include intensive care for severe or life-threatening CRS. Table 3: Recommendations for Management of Cytokine Release Syndrome Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria for grading CRS.
Presenting Symptoms Recommendations Grade 1 Fever ≥100.4ºF (38ºC) Attributed to CRS. Withhold LYNOZYFIC until CRS resolves. When CRS resolves, resume LYNOZYFIC.
Administer pretreatment medications prior to next dose., Follow the recommendations in Table 2 for restarting dosing. Neurologic Toxicity, including ICANS Management recommendations for ICANS and neurologic toxicity are summarized in Table 4 and Table 5. At the first sign of suspected neurologic toxicity, including ICANS, withhold LYNOZYFIC and consider consultation with neurologist and other specialists for further evaluation and management.
Rule out other causes of neurologic symptoms. Provide supportive therapy, which may include intensive care for severe or life - threatening ICANS. Manage per current practice guidelines.
Table 4: s Management recommendations for other adverse reactions are summarized in Table 5. Table 5:
Preparation and Administration Preparation
Use aseptic technique to prepare LYNOZYFIC. Each vial is intended for one time use only. Do not shake.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. LYNOZYFIC is a clear to slightly opalescent, colorless to pale yellow solution. Discard the vial if the solution is cloudy, discolored, or contains particulate matter.
Determine the dose, total volume of LYNOZYFIC solution, and the number of LYNOZYFIC vials needed (see Table 6 ). Dilution Withdraw the desired dose from the vial of LYNOZYFIC and transfer into an intravenous infusion bag of 0.9% Sodium Chloride Injection, according to Table 6. Discard any unused portion left in the vial.
Mix diluted solution by gentle inversion. Do not shake the solution. Table 6: Dilution of LYNOZYFIC Diluted LYNOZYFIC Storage Use diluted LYNOZYFIC immediately.
If not used immediately, store the solution: at room temperature up to 25°C (77°F) for no more than 8 hours from preparation to the start of the infusion. Or under refrigeration at 2°C to 8°C (36°F to 46°F) for no more than 48 hours from preparation to the start of the infusion. Do not freeze.
Do not shake. Administration Administer as an intravenous infusion only. Refer to Dosage and Administration for infusion rates.
Connect the prepared intravenous infusion bag containing the final LYNOZYFIC solution to intravenous tubing constructed of PVC, polyethylene (PE)-lined PVC, or polyurethane (PU). Use of a 0.2-micron to 5-micron polyethersulfone (PES) filter is required. Prime with LYNOZYFIC to the end of the intravenous tubing.
Do not mix LYNOZYFIC with other drugs or concurrently administer other drugs through the same intravenous line. Upon completion of LYNOZYFIC infusion, flush the infusion line with an adequate volume of sterile 0.9% Sodium Chloride Injection to ensure that the entire contents of the infusion bag are administered. Total infusion time should include flushing of the infusion line.
| Dosing Schedule | Day | Dose of LYNOZYFIC | |
|---|---|---|---|
| Step-Up Dosing Schedule | Day 1 | Step-up dose 1 | 5 mg |
| Day 8 | Step-up dose 2 | 25 mg | |
| Day 15 | First treatment dose | 200 mg | |
| Weekly Dosing Schedule | One week after Day 15 treatment dose and once weekly from Week 4 to Week 13 for 10 treatment doses | Second and subsequent treatment doses | 200 mg |
| Biweekly (Every 2 Weeks) Dosing Schedule | Week 14 and every 2 weeks thereafter | Subsequent treatment doses | 200 mg |
| Patients who have achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg | |||
| Every 4 Weeks Dosing Schedule | At Week 24 or after and every 4 weeks thereafter | Subsequent treatment doses | 200 mg |
| Dosing Schedule | Day Weekly doses should be at least 5 days apart. Biweekly doses should be at least 10 days apart. Every 4-week doses should be at least 24 days apart. | LYNOZYFIC Dose | Duration of Infusion | |
|---|---|---|---|---|
| Step-up Dosing Schedule | Day 1 | Step-up dose 1 | 5 mg | 4 hours |
| Day 8 | Step-up dose 2 | 25 mg | ||
| Day 15 | First treatment dose | 200 mg | ||
| Weekly Dosing Schedule | One week after Day 15 treatment dose and once weekly from Week 4 to Week 13 for 10 treatment doses | Second and subsequent treatment doses | 200 mg | 1 hour for the second treatment dose, and 30 minutes for subsequent doses For patients who experienced CRS with the previous dose of LYNOZYFIC, the duration of infusion should be maintained at the duration of the previous infusion; reduce the duration of infusion sequentially in subsequent doses in patients who do not experience CRS (e.g., 4 hours, 1 hour, then 30 minutes). |
| Biweekly (Every 2 Weeks) Dosing Schedule | Week 14 and every 2 weeks thereafter | Subsequent treatment doses | 200 mg | 30 minutes |
| Patients who have achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg | ||||
| Every 4 Weeks Dosing Schedule | At Week 24 or after and every 4 weeks thereafter | 200 mg | 30 minutes | |
| Last Dose Administered | Time since the last dose administered Consider benefit-risk of restarting LYNOZYFIC in patients who require a dose delay of more than 30 days. | Action for next dose. (For CRS/IRR or ICANS, refer to the dose modifications in Table 3, Table 4, and Table 5.) |
|---|---|---|
| NOTE: Administer pre-treatment medications prior to step-up dose 1, step-up dose 2, the first treatment dose, the second treatment dose, and if indicated, subsequent treatment doses [see Dosage and Administration (2.3) ]. | ||
| 5 mg | 14 days or less | Administer 25 mg |
| Greater than 14 days | Restart step-up dosing from 5 mg | |
| 25 mg | 14 days or less | Administer 200 mg |
| Greater than 14 days and less than or equal to 28 days | Restart step-up dosing from 25 mg | |
| Greater than 28 days | Restart step-up dosing from 5 mg | |
| 200 mg | 49 days or less | Administer 200 mg |
| Greater than 49 days | Restart step-up dosing from 5 mg | |
| Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) criteria for grading CRS (2019). | Presenting Symptoms | Recommendations |
|---|---|---|
| Grade 1 | Fever ≥100.4ºF (38ºC) Attributed to CRS. Fever may not always be present concurrently with hypotension or hypoxia as it may be masked by interventions such as steroids, antipyretics, or anticytokine therapy. | Withhold LYNOZYFIC until CRS resolves. Provide supportive care, which may include intensive care. When CRS resolves, resume LYNOZYFIC. Administer pretreatment medications prior to next dose [see Dosage and Administration (2.3) ]., Follow the recommendations in Table 2 for restarting dosing. |
| Grade 2 | Fever ≥100.4°F (38°C) with: Hypotension responsive to fluids and not requiring vasopressors and/or hypoxia requiring low-flow oxygen Low-flow oxygen defined as oxygen delivered at less than 6 L/minute: high-flow oxygen defined as oxygen delivered at greater than or equal to 6 L/minute. by nasal cannula or blow-by | Withhold LYNOZYFIC until CRS resolves. Provide supportive care, which may include intensive care. When CRS resolves, resume treatment with LYNOZYFIC., Consider a decrease in infusion rate up to 50% (no more than 6 hours total) when resuming treatment. Increase rate on subsequent infusions if tolerated. Monitor patients within proximity of a healthcare facility for 24 hours following this dose, and consider hospitalization. |
| Grade 3 | Fever ≥100.4°F (38°C) with: Hypotension requiring a vasopressor (with or without vasopressin) and/or hypoxia requiring high-flow oxygen by nasal cannula, face mask, non-rebreather mask, or Venturi mask. | Withhold LYNOZYFIC until CRS resolves. Provide supportive care, which may include intensive care. When CRS resolves, resume treatment with LYNOZYFIC at reduced dose:, If the last dose administered was 5 mg, administer 2.5 mg. If the last dose administered was 25 mg, restart step-up dosing from 5 mg. If the last dose administered was 200 mg, refer to Table 2 for recommendations regarding restarting therapy based on time since the last dose. Decrease infusion rate up to 50% (no more than 6 hours total). Hospitalize for 24 hours after the administration for this dose. After resuming treatment, if the administered dose is tolerated: Continue with the next dose of the recommended dosing regimen per Table 1. If the full dose is tolerated, infusion rate can be increased to the rate prior to the adverse reaction. Permanently discontinue LYNOZYFIC if Grade 3 CRS recurs with subsequent infusions. |
| Grade 4 | Fever ≥100.4°F (38°C) with: Hypotension requiring multiple vasopressors (excluding vasopressin) and/or hypoxia requiring oxygen by positive pressure (e.g., continuous positive airway pressure (CPAP), bilevel positive airway pressure (BiPAP), intubation, and mechanical ventilation). | Discontinue LYNOZYFIC permanently. CRS should be managed per Grade 3 recommendations. |
| Other | AST/ALT greater than 5 times ULN associated with CRS Grade 3 or less | Withhold LYNOZYFIC until CRS resolves and AST/ALT are less than 3 times ULN if baseline was normal or 1.5 to 3 times baseline if baseline was abnormal. Provide supportive care, which may include intensive care, and monitor. No change in dose is needed in patients without CRS symptoms with transaminase levels that are trending towards baseline within 7 days. If values do not trend towards baseline in 7 days, decrease the dose. See infusion rate information by CRS grade. |
| Grade Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS. | Presenting Symptoms Management is determined by the most severe event, not attributable to any other cause. | Recommendations |
|---|---|---|
| Grade 1 | ICE If patient is arousable and able to perform Immune Effector Cell-Associated Encephalopathy (ICE) Assessment, assess: Orientation (oriented to year, month, city, hospital=4 points); Naming (name 3 objects, e.g., point to clock, pen, button=3 points); Following Commands (e.g., "show me 2 fingers" or "close your eyes and stick out your tongue"=1 point); Writing (ability to write a standard sentence=1 point); and Attention (count backwards from 100 by ten=1 point). If patient is unarousable and unable to perform ICE Assessment (Grade 4 ICANS)=0 points. score 7-9, or depressed level of consciousness Not attributable to any other cause.: awakens spontaneously. | Withhold until neurologic symptoms resolve or return to baseline. Follow the recommendations in Table 2 for restarting dosing. Provide supportive therapy. Manage per current practice guidelines. Consider non-sedating, anti-seizure medications for seizure prophylaxis. |
| Grade 2 | ICE score 3-6, or depressed level of consciousness: awakens to voice. | Withhold until neurologic symptoms resolve or return to baseline. Provide supportive therapy. Manage per current practice guidelines. Administer dexamethasone All references to dexamethasone administration are dexamethasone or equivalent. 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Consider non-sedating, anti-seizure medications for seizure prophylaxis. Monitor patients within proximity of a healthcare facility for 24 hours following the next dose of LYNOZYFIC and consider hospitalization. |
| Grade 3 | ICE score 0-2, or depressed level of consciousness: awakens only to tactile stimulus, or seizures, either: any clinical seizure, focal or generalized, that resolves rapidly, or non-convulsive seizures on electroencephalogram (EEG) that resolve with intervention, or raised intracranial pressure: focal/local edema on neuroimaging. | Withhold until neurologic symptoms resolve or return to baseline. Provide supportive therapy, which may include intensive care. Manage per current practice guidelines. Consider neurology evaluation. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Consider non-sedating, anti-seizure medications for seizure prophylaxis. Permanently discontinue LYNOZYFIC for recurrent Grade 3 ICANS. Resume treatment with LYNOZYFIC at a reduced dose If the last dose administered was 5 mg, administer 2.5 mg. If the last dose administered was 25 mg, restart step-up dosing from 5 mg. If the last dose administered was 200 mg, refer to Table 2 for recommendations regarding restarting therapy based on time since the last dose. and hospitalize for 24 hours after the administration of the dose. After resuming treatment, if the administered dose is tolerated, continue with the next dose of the recommended dosing regimen per Table 1. |
| Grade 4 | ICE score 0, or depressed level of consciousness: either: patient is unarousable or requires vigorous or repetitive tactile stimuli to arouse, or stupor or coma, or seizures, either: life-threatening prolonged seizure (>5 minutes), or repetitive clinical or electrical seizures without return to baseline in between, or motor findings: deep focal motor weakness such as hemiparesis or paraparesis, or raised intracranial pressure/cerebral edema, with signs/ symptoms such as: diffuse cerebral edema on neuroimaging, or decerebrate or decorticate posturing, or cranial nerve VI palsy, or papilledema, or Cushing's triad. | Permanently discontinue LYNOZYFIC. Provide supportive therapy, which may include intensive care. Manage per current practice guidelines. Consider neurology evaluation. Administer dexamethasone 10 mg intravenously every 6 hours. Continue dexamethasone use until resolution to Grade 1 or less, then taper. Consider non-sedating, anti-seizure medications for seizure prophylaxis. |
| Adverse Reaction | Severity Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 5.0 | Recommendations |
|---|---|---|
| Infusion-Related Reactions | Grade 2 | Stop infusion and treat symptoms. May resume treatment with the remaining infusion (total infusion time must not exceed 6 hours total) when symptoms are Grade 1 or baseline. Consider decreasing infusion rate by up to 50% when resuming treatment. If tolerated, infusion rate can be increased with subsequent doses. |
| Grade 3 | Stop infusion and treat symptoms. May resume when symptoms are Grade 1 or baseline. After resolution of the adverse event, follow the recommendations: Decrease the infusion rate up to 50% (no more than 6 hours total). Resume at reduced dose. If the last dose administered was 5 mg, administer 2.5 mg. If the last dose administered was 25 mg, restart step-up dosing from 5 mg. If the last dose administered was 200 mg, refer to Table 2 for recommendations regarding restarting therapy based on time since the last dose. If the administered dose is tolerated, continue with the next dose of the recommended dosing regimen at the decreased infusion rate. Infusion rate can be increased if tolerated. Permanently discontinue LYNOZYFIC if Grade 3 IRR recurs with subsequent infusions. | |
| Grade 4 | Permanently discontinue LYNOZYFIC and treat symptoms. | |
| Neurologic Adverse Reactions (excluding ICANS) | Grade 2 | Withhold LYNOZYFIC until symptoms resolve to Grade 1 or baseline. Follow the recommendations in Table 2 for restarting dosing. |
| Grade 3 (First occurrence) | Withhold LYNOZYFIC until Grade 1 or baseline. | |
| Grade 3 (Recurrent) Grade 4 | Permanently discontinue LYNOZYFIC. | |
| Infections | Grades 2 or 3 | Withhold LYNOZYFIC in patients with active infection until the infection improves to Grade 1 or less. |
| Grade 4 | Consider permanent discontinuation of LYNOZYFIC. If treatment is not permanently discontinued, withhold subsequent treatment doses until Grade 1 or baseline. | |
| Other Non-hematologic Adverse Reactions | Grade 3 | Withhold LYNOZYFIC until Grade 1 or baseline. |
| Grade 4 | Consider permanent discontinuation of LYNOZYFIC. If LYNOZYFIC is not permanently discontinued, withhold subsequent treatment doses until Grade 1 or baseline. | |
| Hematologic Adverse Reactions | Platelet count less than 50,000/mcL with bleeding OR less than 25,000/mcL | Withhold LYNOZYFIC until 25,000/mcL or higher and no evidence of bleeding. |
| Absolute neutrophil count less than 1 × 10 9 /L with Grade 2 or higher infection OR less than 0.5 × 10 9 /L | Withhold LYNOZYFIC until 0.5 × 10 9 /L or higher. | |
| Febrile neutropenia | Withhold LYNOZYFIC until neutrophil count is greater than 1 × 10 9 /L and fever resolves. | |
| Hemoglobin less than 8 g/dL | Withhold LYNOZYFIC until hemoglobin is 8 g/dL or higher. |
| LYNOZYFIC dose | LYNOZYFIC vial strength | Volume of LYNOZYFIC to be added to the infusion bag | Size of 0.9% Sodium Chloride Injection Infusion Bag (PVC or PO) |
|---|---|---|---|
| 2.5 mg Modified dose due to adverse reaction. For instructions on when to use the modified dose refer to Table 3, Table 4, and Table 5. | 5 mg/2.5 mL | 1.25 mL | 50 mL |
| 5 mg | 5 mg/2.5 mL | 2.5 mL | 50 mL or 100 mL |
| 25 mg | 5 mg/2.5 mL | 12.5 mL | 50 mL or 100 mL |
| 200 mg | 200 mg/10 mL | 10 mL | 50 mL or 100 mL |
Side Effects of Lynozyfic
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Relapsed or Refractory Multiple Myeloma The safety of LYNOZYFIC was evaluated in LINKER-MM1. In the Phase 2 portion of the study, patients who achieved and maintained VGPR or better at or after Week 24 and received at least 17 doses of 200 mg were able to receive every 4-week dosing.
Serious adverse reactions occurred in 74% of patients who received LYNOZYFIC. Permanent discontinuation of LYNOZYFIC due to adverse reactions occurred in 16% of patients. Adverse reactions leading to discontinuation that occurred in at least 2 patients included sepsis, pneumonia, and encephalopathy.
Dosage interruptions or delays of LYNOZYFIC due to adverse reactions occurred in 74% of patients. The most common adverse reactions (≥20%) were musculoskeletal pain, cytokine release syndrome, cough, upper respiratory tract infection, diarrhea, fatigue, pneumonia, nausea, headache, and dyspnea. The most common Grade 3 to 4 laboratory abnormalities (≥30%) were decreased lymphocyte count, decreased neutrophil count, decreased hemoglobin, and decreased white blood cell count.
Table 7 summarizes the adverse reactions in LINKER-MM1. Table 7: Adverse Reactions (≥10%) in Patients with Relapsed or Refractory Multiple Myeloma Who Received LYNOZYFIC in LINKER-MM1 Clinically significant adverse reactions that occurred in <10% of patients treated with LYNOZYFIC included IRR, motor dysfunction, febrile neutropenia, ICANS, CMV infection, and PML. Table 8 summarizes the laboratory abnormalities in LINKER-MM1.
| Adverse Reaction | LYNOZYFIC (N=117) | |
|---|---|---|
| All Grades (%) | Grade 3 or 4 (%) | |
| Musculoskeletal and connective tissue disorders | ||
| Musculoskeletal pain Includes other related terms. | 53 | 3.4 Only Grade 3 adverse reactions occurred. |
| Immune system disorders | ||
| Cytokine release syndrome | 46 | 0.9 |
| Hypogammaglobulinemia | 13 | 0.9 |
| Respiratory, thoracic and mediastinal disorders | ||
| Cough | 39 | 0 |
| Dyspnea | 21 | 0.9 |
| Nasal congestion | 16 | 0 |
| Infections and infestations | ||
| Upper respiratory tract infection | 35 | 6 |
| Pneumonia Pneumonia includes atypical pneumonia, COVID-19 pneumonia, PJP, pneumonia, pneumonia cytomegaloviral, pneumonia fungal, pneumonia influenzal, and pneumonia viral., Includes fatal outcome. | 28 | 21 |
| COVID-19 | 17 | 5 |
| Urinary tract infections | 16 | 8 |
| Sepsis | 10 | 6 |
| Gastrointestinal disorders | ||
| Diarrhea | 35 | 1.7 |
| Nausea | 23 | 0 |
| Vomiting | 19 | 0 |
| Constipation | 17 | 0 |
| General disorders and administration site conditions | ||
| Fatigue | 34 | 0 |
| Edema | 19 | 0.9 |
| Pyrexia | 17 | 0 |
| Nervous system disorders | ||
| Headache | 22 | 0.9 |
| Encephalopathy, Encephalopathy includes agitation, amnesia, cognitive disorder, confusional state, delirium, depressed level of consciousness, encephalopathy (including hyperammonemic and toxic encephalopathy), irritability, lethargy, memory impairment, mental status changes, somnolence, and excludes ICANS. | 18 | 3.4 |
| Sensory Neuropathy | 13 | 0.9 |
| Metabolism and nutrition disorders | ||
| Decreased appetite | 15 | 0.9 |
| Skin and subcutaneous tissue disorders | ||
| Rash Rash includes dermatitis acneiform, dermatitis contact, drug eruption, erythema, rash, rash erythematous, rash maculo-papular, rash pruritic, and stasis dermatitis. | 15 | 1.7 |
| Psychiatric disorders | ||
| Insomnia | 13 | 0 |
| Vascular disorders | ||
| Hypertension | 10 | 4.3 |
| Laboratory Abnormality Laboratory tests were graded according to NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 5.0. | LYNOZYFIC (N=117) The denominator used to calculate the rate varied from 106 to 117 based on the number of patients with a baseline value and at least one post-treatment value. | |
|---|---|---|
| All Grades (%) | Grades 3 or 4 (%) | |
| Hematology | ||
| Lymphocyte count decreased | 97 | 92 |
| Hemoglobin decreased | 72 | 42 |
| Platelet count decreased | 64 | 19 |
| White blood cell count decreased | 63 | 31 |
| Neutrophil count decreased | 62 | 47 |
| Chemistry | ||
| Aspartate aminotransferase increased | 61 | 10 |
| Phosphorus decreased | 55 | 24 |
| Creatinine increased | 47 | 7 |
| Alanine aminotransferase increased | 46 | 6 |
Warnings & Cautions for Lynozyfic
Cytokine Release Syndrome (CRS) LYNOZYFIC can cause cytokine release syndrome (CRS), which can be serious or life-threatening. Recurrent CRS occurred in 20% (23/117) of patients. Clinical signs and symptoms of CRS included, but were not limited to pyrexia, chills, hypoxia, tachycardia, and hypotension.
Administer pretreatment medications and initiate therapy according to LYNOZYFIC step-up dosing to reduce the incidence and severity of CRS. Monitor patients for signs and symptoms of CRS after infusion. Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur.
At the first sign of CRS, immediately evaluate patients for hospitalization, manage per current practice guidelines, and administer supportive care; withhold LYNOZYFIC until CRS resolves and modify the next dose or permanently discontinue LYNOZYFIC based on severity. Infusion Related Reactions Infusion-related reactions (IRR) may be clinically indistinguishable from manifestations of CRS. In the patients who were treated with the recommended step-up dosing regimen and pretreatment medications, the rate of IRR was 9%.
For IRR, interrupt or slow the rate of infusion or permanently discontinue LYNOZYFIC based on severity of reaction. LYNOZYFIC is available only through a restricted program under a REMS.
Neurologic
Toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome LYNOZYFIC can cause serious or life-threatening neurologic toxicity, including immune effector cell-associated neurotoxicity syndrome (ICANS). Neurologic toxicities included ICANS, depressed level of consciousness, encephalopathy, and toxic encephalopathy. ICANS occurred in 8% of patients who received LYNOZYFIC with the recommended dosing regimen, including Grade 3 events in 2.6%.
Most patients experienced ICANS following step-up dose 1 (5%). Two patients (1.8%) experienced initial ICANS following step-up dose 2 and one patient developed the first occurrence of ICANS following a subsequent full dose of LYNOZYFIC. Recurrent ICANS occurred in one patient.
The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS. The most common clinical signs and symptoms of ICANS are confusion, depressed level of consciousness, and lethargy. Monitor patients for signs and symptoms of neurologic toxicity during treatment.
At the first sign of neurologic toxicity, including ICANS, immediately evaluate the patient; provide supportive therapy and consider further management per current practice guidelines. Due to the potential for neurologic toxicity, including ICANS, patients receiving LYNOZYFIC are at risk of confusion and depressed consciousness. Advise patients to refrain from driving, or operating heavy or potentially dangerous machinery, for 48 hours after completion of each of the step-up doses and in the event of new onset of any neurological symptoms, until symptoms resolve.
Notable requirements of the LYNOZYFIC REMS include the following: Prescribers must be certified with the program by enrolling and completing training. Prescribers must counsel patients receiving LYNOZYFIC about the risk of CRS and neurologic toxicity, including ICANS, and provide patients with LYNOZYFIC Patient Wallet Card. Pharmacies and healthcare settings that dispense LYNOZYFIC must be certified with the LYNOZYFIC REMS program and must verify prescribers are certified through the LYNOZYFIC REMS program.
Wholesalers and distributors must only distribute LYNOZYFIC to certified pharmacies or healthcare settings. Further information about the LYNOZYFIC REMS program is available at lynozyficREMS.com or by telephone at 1-855-212-6391.
Infections LYNOZYFIC can cause serious, life-threatening, or fatal infections. The most common serious infection reported (≥10%) were pneumonia and sepsis. Two cases of progressive multifocal leukoencephalopathy (PML) occurred in patients receiving LYNOZYFIC.
Monitor patients for signs and symptoms of infection and immunoglobulin levels prior to and during treatment with LYNOZYFIC and treat appropriately. Administer prophylactic antimicrobials, antibiotics, antifungals, antivirals, vaccines, and subcutaneous or intravenous immunoglobulin (IVIG) according to guidelines, including prophylaxis for PJP and herpesviruses. Withhold LYNOZYFIC or consider permanent discontinuation of LYNOZYFIC based on severity of the infection.
Neutropenia LYNOZYFIC can cause neutropenia and febrile neutropenia. Febrile neutropenia occurred in 8% of patients. Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local guidelines.
Monitor patients with neutropenia for signs of infection. Withhold LYNOZYFIC based on severity.
Hepatotoxicity LYNOZYFIC can cause hepatotoxicity. Grade 3 or 4 total bilirubin elevations occurred in 1.7% of patients. Liver enzyme elevation can occur with or without concurrent CRS.
Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated.
Embryo-Fetal Toxicity Based on its mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with LYNOZYFIC and for 3 months after the last dose.
Drug Interactions with Lynozyfic
Effects of LYNOZYFIC on Other Drugs Certain
CYP substrates Monitor for toxicity unless otherwise recommended in the Prescribing Information of certain CYP substrates where minimal changes in the concentration may lead to serious adverse reactions when used concomitantly with LYNOZYFIC. Linvoseltamab-gcpt causes the release of cytokines that may suppress cytochrome P450 (CYP) enzyme activity. Concomitant use with LYNOZYFIC increases CYP substrate exposure which may increase the risk of adverse reactions related to these substrates.
Increased CYP substrate exposure is more likely to occur from initiation of the LYNOZYFIC step-up dosing schedule up to 14 days after the first 200 mg dose, and during and after CRS.
Pregnancy Safety for Lynozyfic
Pregnancy Risk Summary Based on the mechanism of action, LYNOZYFIC may cause fetal harm when administered to a pregnant woman. There are no available data on the use of LYNOZYFIC in pregnant women to evaluate for a drug associated risk. No animal reproductive or developmental toxicity studies have been conducted with LYNOZYFIC.
Linvoseltamab-gcpt causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on the finding of B-cell depletion in non-pregnant animals, linvoseltamab-gcpt can cause B-cell lymphocytopenia in infants exposed to linvoseltamab-gcpt in-utero. Human immunoglobulin (IgG) is known to cross the placenta after the first trimester of pregnancy; therefore, linvoseltamab-gcpt has the potential to be transmitted from the mother to the developing fetus.
Advise women of the potential risk to the fetus. LYNOZYFIC is associated with hypogammaglobulinemia, therefore, assessment of immunoglobulin levels in newborns of mothers treated with LYNOZYFIC should be considered. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively.
Pediatric Use of Lynozyfic
Pediatric Use The safety and effectiveness of LYNOZYFIC have not been established in pediatric patients.
Clinical Studies of Lynozyfic
Relapsed or Refractory Multiple Myeloma
The efficacy of LYNOZYFIC was evaluated in patients with relapsed or refractory multiple myeloma in an open-label, multi-center, multi-cohort study: LINKER-MM1 (NCT03761108). The study included patients who had previously received at least 3 prior therapies, including a proteasome inhibitor (PI), an immunomodulatory agent (IMiD), and an anti-CD38 antibody. The study excluded patients with known multiple myeloma brain lesions or meningeal involvement, history of a neurodegenerative condition, history of seizure within 12 months prior to study enrollment, active infection, a history of an allogeneic or autologous stem cell transplantation within 12 weeks, prior BCMA-directed bispecific antibody therapy, prior bispecific T-cell engaging therapy, or prior BCMA CAR-T cell therapy.
Patients were treated until disease progression or unacceptable toxicity. The efficacy population included 80 patients who had received at least four prior lines of therapy. The International Staging System (ISS) at study entry was Stage I in 39%, Stage II in 36%, and Stage III in 19%.
High-risk cytogenetics (presence of del(17p), t(4;14) and t(14;16)) were present in 40% of patients. Eighteen percent of patients had extramedullary disease at baseline. Sixty-five percent of patients received prior stem cell transplantation.
Seventy-nine percent of patients were triple-class refractory (refractory to a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody). Thirteen percent of patients were previously treated with a BCMA antibody-drug conjugate. Efficacy was established based on objective response rate (ORR) as determined by blinded independent review committee (IRC), as measured using the International Myeloma Working Group (IMWG) criteria (see Table 10 ).
The median time to first response was 0.95 months (range: 0.5 to 6 months). With a median follow-up of 11.3 months among responders, the estimated duration of response (DOR) rate was months and months. Table 10: Efficacy Results for LINKER-MM1
| Efficacy Endpoints | LYNOZYFIC N=80 |
|---|---|
| CI=confidence interval; NE=not estimable | |
| Objective Response Rate (ORR) % (n) | 70% (56) |
| (95% CI) | (59,80) |
| Complete response (CR) or better, % (n) | 45% (36) |
| (95% CI) | (34,57) |
| Stringent complete response (sCR), % (n) | 39% (31) |
| Complete response (CR), % (n) | 6% (5) |
| Very good partial response (VGPR) % (n) | 19% (15) |
| Partial response (PR), % (n) | 6% (5) |
| Duration of Response (DOR) Based on Kaplan-Meier estimation. | |
| Median, months (95% CI) | NR (12, NE) |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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